WAT-free mice: diabetes without obesity
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9152 USA
This extract was created in the absence of an abstract.
Two papers appearing in this issue report the generation of transgenic mice largely devoid of white adipose tissue (WAT). In both cases the resulting mice display anatomical and physiological properties very similar to human patients suffering from generalized lipodystrophy. Such patients lack WAT, a condition resulting from either genetic or autoimmune etiologies, and are severely diabetic (Foster 1994; Seip and Trygstad 1996). The present reports provide fresh and interesting observations regarding the physiological consequences of life without fat and, moreover, establish animal models that offer new opportunities for the study of type 2 diabetes.
How was it possible to engineer WAT-free laboratory mice? The two teams, headed by Brown and Goldstein in Texas (Shimomura et al. 1998) and Vinson at the National Institutes of Health (NIH) (Moitra et al. 1998), attacked the problem using similar strategies. The Texans directed adipocyte-specific expression of a truncated, constitutively active form of SREBP1c, a transcription factor involved in the regulation of genes required for the biosynthesis of both cholesterol and fatty acids. The Federalists likewise directed the expression of a modified transcription factor in WAT. In the latter case, the team utilized clever methods to inhibit the function of endogenous members of the Jun and CCAAT/enhancer-binding protein (C/EBP) families of transcription factors. Expression of these dominant-positive and dominant-negative transcription factors were similarly directed to brown adipose tissue (BAT) and WAT by the use of regulatory sequences associated with the adipocyte-specific aP2 gene (Ross et al. 1990). The resulting transgenic mice were remarkably similar—WAT-free, profoundly insulin resistant, and rampantly diabetic.
Before delving into the interesting physiological and anatomical abnormalities observed in WAT-free mice, it is useful to review the respective experimental approaches in the context of the gene regulatory pathways that were perturbed. Moitra and colleagues made use of an artificial transcription factor designated …
